tbuckley/cabot-search huggingface dataset:
Clinician Job Satisfaction After Peer Comparison Feedback
Authors: Jason N. Doctor, Noah J. Goldstein, Craig R. Fox, Jeffrey A. Linder, Stephen D. Persell, Emily P. Stewart, Tara K. Knight, Daniella Meeker
Journal: JAMA Network Open (2023)

Importance Interventions that improve clinician performance through feedback should not contribute to job dissatisfaction or staff turnover. Measurement of job satisfaction may help identify interventions that lead to this undesirable consequence. Objective To evaluate whether mean job satisfaction was less than the margin of clinical significance among clinicians who received social norm feedback (peer comparison) compared with clinicians who did not. Design, Setting, and Participants This secondary, preregistered, noninferiority analysis of a cluster randomized trial compared 3 interventions to reduce inappropriate antibiotic prescribing in a 2 × 2 × 2 factorial design from November 1, 2011, to April 1, 2014. A total of 248 clinicians were enrolled from 47 clinics. The sample size for this analysis was determined by the number of nonmissing job satisfaction scores from the original enrolled sample, which was 201 clinicians from 43 clinics. Data analysis was performed from October 12 to April 13, 2022. Interventions Feedback comparing individual clinician performance to top-performing peers, delivered in monthly emails (peer comparison). Main Outcomes and Measures The primary outcome was a response to the following statement: “Overall, I am satisfied with my current job.” Responses ranged from 1 (strongly disagree) to 5 (strongly agree). Results A total of 201 clinicians (response rate, 81%) from 43 of the 47 clinics (91%) provided a survey response about job satisfaction. Clinicians were primarily female (n = 129 [64%]) and board certified in internal medicine (n = 126 [63%]), with a mean (SD) age of 48 (10) years. The clinic-clustered difference in mean job satisfaction was greater than −0.32 (β = 0.11; 95% CI, −0.19 to 0.42; P = .46). Therefore, the preregistered null hypothesis that peer comparison is inferior by resulting in at least a 1-point decrease in job satisfaction by 1 in 3 clinicians was rejected. The secondary null hypothesis that job satisfaction was similar among clinicians randomized to social norm feedback was not able to be rejected. The effect size did not change when controlling for other trial interventions ( t = 0.08; P = .94), and no interaction effects were observed. Conclusions and Relevance In this secondary analysis of a randomized clinical trial, peer comparison did not lead to lower job satisfaction. Features that may have protected against dissatisfaction include clinicians’ agency over the performance measure, privacy of individual performance, and allowing all clinicians to achieve top performance. Trial Registration ClinicalTrials.gov Identifiers: NCT05575115 and NCT01454947
FDA Approval Summary: Futibatinib for Unresectable Advanced or Metastatic, Chemotherapy Refractory Intrahepatic Cholangiocarcinoma with FGFR2 Fusions or Other Rearrangements
Authors: Shruti U. Gandhy, Sandra J. Casak, Sirisha L. Mushti, Joyce Cheng, Sriram Subramaniam, Hong Zhao, Miao Zhao, Youwei Bi, Guansheng Liu, Jianghong Fan, Oluseyi Adeniyi, Rosane Charlab, Dubravka Kufrin, Matthew D. Thompson, Kristin Jarrell, Doris Auth, Steven J. Lemery, Richard Pazdur, Paul G. Kluetz, Lola A. Fashoyin-Aje
Journal: Clinical Cancer Research (2023)

Abstract On September 30, 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions or other rearrangements. Approval was based on Study TAS-120–101, a multicenter open-label, single-arm trial. Patients received futibatinib 20-mg orally once daily. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1. ORR was 42% (95% confidence interval, 32%–52%). Median DoR was 9.7 months. Adverse reactions occurring in ≥30% patients were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, and abdominal pain. The most common laboratory abnormalities (≥50%) were increased phosphate, increased creatinine, decreased hemoglobin, and increased glucose. Ocular toxicity (including dry eye, keratitis, and retinal epithelial detachment) and hyperphosphatemia are important risks of futibatinib, which are listed under Warnings and Precautions. This article summarizes the FDA's thought process and data supporting the approval of futibatinib.
Targeting BCL2 Overcomes Resistance and Augments Response to Aurora Kinase B Inhibition by AZD2811 in Small Cell Lung Cancer
Authors: Kavya Ramkumar, Azusa Tanimoto, Carminia M. Della Corte, C. Allison Stewart, Qi Wang, Li Shen, Robert J. Cardnell, Jing Wang, Urszula M. Polanska, Courtney Andersen, Jamal Saeh, J. Elizabeth Pease, Jon Travers, Giulia Fabbri, Carl M. Gay, Jelena Urosevic, Lauren A. Byers
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy. Experimental Design: Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. Proteomic and transcriptomic profiles were analyzed to identify candidate biomarkers of response and resistance. Effects on polyploidy, DNA damage, and apoptosis were measured by flow cytometry and Western blotting. Rational drug combinations were validated in SCLC cell lines and PDX models. Results: AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression. Importantly, high BCL2 expression predicted resistance to AURKB inhibitor response in SCLC, independent of cMYC status. AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax, an FDA-approved BCL2 inhibitor. Conclusions: BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models.
Characterizing Evolutionary Dynamics Reveals Strategies to Exhaust the Spectrum of Subclonal Resistance in EGFR-Mutant Lung Cancer
Authors: Nina Müller, Carina Lorenz, Jenny Ostendorp, Felix S. Heisel, Ulrich P. Friese, Maria Cartolano, Dennis Plenker, Hannah Tumbrink, Alena Heimsoeth, Philipp Baedeker, Jonathan Weiss, Sandra Ortiz-Cuaran, Reinhard Büttner, Martin Peifer, Roman K. Thomas, Martin L. Sos, Johannes Berg, Johannes Brägelmann
Journal: Cancer Research (2023)

Abstract The emergence of resistance to targeted therapies restrains their efficacy. The development of rationally guided drug combinations could overcome this currently insurmountable clinical challenge. However, our limited understanding of the trajectories that drive the outgrowth of resistant clones in cancer cell populations precludes design of drug combinations to forestall resistance. Here, we propose an iterative treatment strategy coupled with genomic profiling and genome-wide CRISPR activation screening to systematically extract and define preexisting resistant subpopulations in an EGFR-driven lung cancer cell line. Integrating these modalities identifies several resistance mechanisms, including activation of YAP/TAZ signaling by WWTR1 amplification, and estimates the associated cellular fitness for mathematical population modeling. These observations led to the development of a combination therapy that eradicated resistant clones in large cancer cell line populations by exhausting the spectrum of genomic resistance mechanisms. However, a small fraction of cancer cells was able to enter a reversible nonproliferative state of drug tolerance. This subpopulation exhibited mesenchymal properties, NRF2 target gene expression, and sensitivity to ferroptotic cell death. Exploiting this induced collateral sensitivity by GPX4 inhibition clears drug-tolerant populations and leads to tumor cell eradication. Overall, this experimental in vitro data and theoretical modeling demonstrate why targeted mono- and dual therapies will likely fail in sufficiently large cancer cell populations to limit long-term efficacy. Our approach is not tied to a particular driver mechanism and can be used to systematically assess and ideally exhaust the resistance landscape for different cancer types to rationally design combination therapies. Significance: Unraveling the trajectories of preexisting resistant and drug-tolerant persister cells facilitates the rational design of multidrug combination or sequential therapies, presenting an approach to explore for treating EGFR-mutant lung cancer.
Treatment Strategies for Cardiomyopathy in Children: A Scientific Statement From the American Heart Association
Authors: Carmel Bogle, Steven D. Colan, Shelley D. Miyamoto, Swati Choudhry, Nathanya Baez-Hernandez, Molly M. Brickler, Brian Feingold, Ashwin K. Lal, Teresa M. Lee, Charles E. Canter, Steven E. Lipshultz
Journal: Circulation (2023)

This scientific statement from the American Heart Association focuses on treatment strategies and modalities for cardiomyopathy (heart muscle disease) in children and serves as a companion scientific statement for the recent statement on the classification and diagnosis of cardiomyopathy in children. We propose that the foundation of treatment of pediatric cardiomyopathies is based on these principles applied as personalized therapy for children with cardiomyopathy: (1) identification of the specific cardiac pathophysiology; (2) determination of the root cause of the cardiomyopathy so that, if applicable, cause-specific treatment can occur (precision medicine); and (3) application of therapies based on the associated clinical milieu of the patient. These clinical milieus include patients at risk for developing cardiomyopathy (cardiomyopathy phenotype negative), asymptomatic patients with cardiomyopathy (phenotype positive), patients with symptomatic cardiomyopathy, and patients with end-stage cardiomyopathy. This scientific statement focuses primarily on the most frequent phenotypes, dilated and hypertrophic, that occur in children. Other less frequent cardiomyopathies, including left ventricular noncompaction, restrictive cardiomyopathy, and arrhythmogenic cardiomyopathy, are discussed in less detail. Suggestions are based on previous clinical and investigational experience, extrapolating therapies for cardiomyopathies in adults to children and noting the problems and challenges that have arisen in this experience. These likely underscore the increasingly apparent differences in pathogenesis and even pathophysiology in childhood cardiomyopathies compared with adult disease. These differences will likely affect the utility of some adult therapy strategies. Therefore, special emphasis has been placed on cause-specific therapies in children for prevention and attenuation of their cardiomyopathy in addition to symptomatic treatments. Current investigational strategies and treatments not in wide clinical practice, including future direction for investigational management strategies, trial designs, and collaborative networks, are also discussed because they have the potential to further refine and improve the health and outcomes of children with cardiomyopathy in the future.
What is the best score for predicting difficult laparoscopic cholecystectomy? A diagnostic trial study
Authors: Camilo Ramírez-Giraldo, Andrés Isaza-Restrepo, Danny Conde Monroy, Andrea Carolina Castillo-Barbosa, Juan José Rubio-Avilez, Isabella Van-Londoño
Journal: International Journal of Surgery (2023)

Background: Multiple scores have been created in order to predict difficult cholecystectomy, nonetheless there is not a consensuated standard on which to use. The importance of a predictive score to be able to establish a difficult cholecystectomy would be a relevant instrument in order to better inform the patient, properly call for help when needed, choose the correct staff, and schedule and plan the surgical procedure accordingly. Methods: A diagnostic trial study was performed. All different predictive scores for difficult cholecystectomy were calculated for each patient. The correlation between the preoperative score and cholecystectomies considered as "difficult" were measured estimating the preoperative score's predictive value using a ROC curve in order to predict findings for difficult cholecystectomy. Results: A total of 635 patients between 2014-2021 were selected. Selected patients had a mean age of 55.0 (IQR: 28.00) and were mostly female (64.25%). Surgical outcomes of patients with difficult cholecystectomy had statistically significant higher rates of subtotal cholecystectomies, drain usage, complications and reinterventions, prolonged surgical times, and longer hospital stay. When analyzing the predictive value on each of the different scores applied, score 4 had the highest performance for predicting difficult cholecystectomy with an AUC=0.783 (CI 95% 0.745-0.822). Conclusions: Difficult cholecystectomies are associated with worse surgical outcomes. The standardization and use of predictive scores for difficult cholecystectomy must be implemented in order to improve surgical outcomes as a result of more meticulous planning when scheduling the procedure.
A commentary on “perioperative versus postoperative calcium and vitamin d supplementation to prevent symptomatic hypocalcemia after total thyroidectomy: a randomized placebo controlled trial”
Authors: Zhe-Ming Zhao, Chun-Dong Zhang
Journal: International Journal of Surgery (2023)

Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital, China Medical University, No.4 Chongshan East Road, Shenyang 110032, China. Telephone: +86-189-0091-2404. E-mail address: [email protected] (C-D. Zhang). This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/
Not every estimate counts – evaluation of cell composition estimation approaches in brain bulk tissue data
Authors: Lilah Toker, Gonzalo S. Nido, Charalampos Tzoulis
Journal: Genome Medicine (2023)

Abstract Background Variation in cell composition can dramatically impact analyses in bulk tissue samples. A commonly employed approach to mitigate this issue is to adjust statistical models using estimates of cell abundance derived directly from omics data. While an arsenal of estimation methods exists, the applicability of these methods to brain tissue data and whether or not cell estimates can sufficiently account for confounding cellular composition has not been adequately assessed. Methods We assessed the correspondence between different estimation methods based on transcriptomic (RNA sequencing, RNA-seq) and epigenomic (DNA methylation and histone acetylation) data from brain tissue samples of 49 individuals. We further evaluated the impact of different estimation approaches on the analysis of H3K27 acetylation chromatin immunoprecipitation sequencing (ChIP-seq) data from entorhinal cortex of individuals with Alzheimer’s disease and controls. Results We show that even closely adjacent tissue samples from the same Brodmann area vary greatly in their cell composition. Comparison across different estimation methods indicates that while different estimation methods applied to the same data produce highly similar outcomes, there is a surprisingly low concordance between estimates based on different omics data modalities. Alarmingly, we show that cell type estimates may not always sufficiently account for confounding variation in cell composition. Conclusions Our work indicates that cell composition estimation or direct quantification in one tissue sample should not be used as a proxy to the cellular composition of another tissue sample from the same brain region of an individual—even if the samples are directly adjacent. The highly similar outcomes observed among vastly different estimation methods, highlight the need for brain benchmark datasets and better validation approaches. Finally, unless validated through complementary experiments, the interpretation of analyses outcomes based on data confounded by cell composition should be done with great caution, and ideally avoided all together.
Comparing Risk for Second Primary Cancers After Intensity-Modulated vs 3-Dimensional Conformal Radiation Therapy for Prostate Cancer, 2002-2015
Authors: Kishan J. Pithadia, Pragati G. Advani, Deborah E. Citrin, Justin E. Bekelman, Diana R. Withrow, Amy Berrington de Gonzalez, Lindsay M. Morton, Sara J. Schonfeld
Journal: JAMA Oncology (2023)

Compared with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT) can spare nearby tissue but may result in increased scatter radiation to distant normal tissue, including red bone marrow. It is unclear whether second primary cancer risk varies by radiotherapy type.
Diagnosis and Management of Tropomyosin Receptor Kinase Fusion-Positive Thyroid Carcinomas
Authors: Robert Haddad, Rossella Elisei, Ana O. Hoff, Zhiyan Liu, Fabian Pitoia, Giancarlo Pruneri, Peter M. Sadow, Fernando Soares, Andrew Turk, Michelle D. Williams, Lori J. Wirth, Maria E. Cabanillas
Journal: JAMA Oncology (2023)

Thyroid epithelial malignant neoplasms include differentiated thyroid carcinomas (papillary, follicular, and oncocytic), follicular-derived high-grade thyroid carcinomas, and anaplastic and medullary thyroid carcinomas, with additional rarer subtypes. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions has fostered developments in precision oncology, with the approval of tropomyosin receptor kinase inhibitors (larotrectinib and entrectinib) for patients with solid tumors, including advanced thyroid carcinomas, harboring NTRK gene fusions.The relative rarity and diagnostic complexity of NTRK gene fusion events in thyroid carcinoma present several challenges for clinicians, including variable access to robust methodologies for comprehensive NTRK fusion testing and poorly defined algorithms of when to test for such molecular alterations. To address these issues in thyroid carcinoma, 3 consensus meetings of expert oncologists and pathologists were convened to discuss diagnostic challenges and propose a rational diagnostic algorithm. Per the proposed diagnostic algorithm, NTRK gene fusion testing should be considered as part of the initial workup for patients with unresectable, advanced, or high-risk disease as well as following the development of radioiodine-refractory or metastatic disease; testing by DNA or RNA next-generation sequencing is recommended. Detecting the presence of NTRK gene fusions is important to identify patients eligible to receive tropomyosin receptor kinase inhibitor therapy.This review provides practical guidance for optimal integration of gene fusion testing, including NTRK gene fusion testing, to inform the clinical management in patients with thyroid carcinoma.
Proteomic analysis of the esophageal epithelium reveals key features of eosinophilic esophagitis pathophysiology
Authors: Francisca Molina‐Jiménez, Lola Ugalde‐Triviño, Laura Arias‐González, Carlos Relaño‐Rupérez, Sergio Casabona, María Teresa Pérez‐Fernández, Verónica Martín‐Domínguez, Jennifer Fernández‐Pacheco, Emilio José Laserna‐Mendieta, Patricia Muñoz‐Hernández, Ángel Arias‐Arias, Ainara Cano, Javier Muñoz, Alfredo J. Lucendo, Cecilio Santander, Pedro Majano
Journal: Allergy (2023)

Eosinophilic esophagitis (EoE) is a chronic non-IgE-mediated allergic disease of the esophagus. An unbiased proteomics approach was performed to investigate pathophysiological changes in esophageal epithelium. Additionally, an RNAseq-based transcriptomic analysis in paired samples was also carried out.Total proteins were purified from esophageal endoscopic biopsies in a cohort of adult EoE patients (n = 25) and healthy esophagus controls (n = 10). Differentially accumulated (DA) proteins in EoE patients compared to control tissues were characterized to identify altered biological processes and signaling pathways. Results were also compared with a quantitative proteome dataset of the human esophageal mucosa. Next, results were contrasted with those obtained after RNAseq analysis in paired samples. Finally, we matched up protein expression with two EoE-specific mRNA panels (EDP and Eso-EoE panel).A total of 1667 proteins were identified, of which 363 were DA in EoE. RNA sequencing in paired samples identified 1993 differentially expressed (DE) genes. Total RNA and protein levels positively correlated, especially in DE mRNA-proteins pairs. Pathway analysis of these proteins in EoE showed alterations in immune and inflammatory responses for the upregulated proteins, and in epithelial differentiation, cornification and keratinization in those downregulated. Interestingly, a set of DA proteins, including eosinophil-related and secreted proteins, were not detected at the mRNA level. Protein expression positively correlated with EDP and Eso-EoE, and corresponded with the most abundant proteins of the human esophageal proteome.We unraveled for the first time key proteomic features involved in EoE pathogenesis. An integrative analysis of transcriptomic and proteomic datasets provides a deeper insight than transcriptomic alone into understanding complex disease mechanisms.
Lessons from a recent multicountry iatrogenic botulism outbreak
Authors: Fabrizio Anniballi
Journal: Eurosurveillance (2023)

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